Nicotine consumption is linked to improvements in cognitive functions such as attention and memory, as well as improvements in symptoms for those suffering from disorders such as anxiety, depression and schizophrenia. Furthermore, nicotinic receptors in the central nervous system have been implicated in such wildly disparate conditions such as pain and neurodegenerative disorders like Parkinson's and Alzheimer's disease. Therefore, finding pharmaceutical compounds, which act on nicotinic receptors, without the side effects of nicotine including addiction, would constitute an important advancement for mental health. With SBIR funding, we will accelerate the ongoing cell- based drug discovery process by creating improved nicotinic receptor cell lines for high throughput screening of small compound libraries. The discovery of a novel molecular handle on these receptors, allows for the selective targeting of nicotinic receptor subtypes involved in disease. We propose to recapitulate the entire receptor complex including key accessory molecules in creating high functioning cell lines that represent a more complete state of nicotinic receptors as they occur in the nervous system. This innovative approach is likely to yield a higher percentage of novel classes of pharmaceutically active compounds for lead optimization than those obtained with traditional methods. PUBLIC HEALTH RELEVANCE The aim of the proposed project is for the development of therapeutic treatments of neurological disorders with a cholinergic component. Cholinergic therapeutics are relevant in the area of cognitive disorders, anxiety disorders such as depression, dementias, schizophrenia, in pain disorders, and neurodegenerative disorders including Parkinson's disease and Alzheimer's disease (Sacco et al., 2004, Newhouse et al., 2004, Lloyd and Williams, 2000).